Minocycline is a member of the broad spectrum tetracycline antibiotics, which has a broader spectrum than the other members of this group of compounds.
Minocycline is widely used in therapy, primarily to treat acne and rosacea at a once daily dose of 100 mg. Minocycline has a unique biological activity profile: it has both antibacterial and anti-inflammatory proprieties.
The preparation of minocycline is, for example, disclosed in U.S. Pat. Nos. 3,148,212; 3,226,436 and 4,849,136.
In general minocycline may be used as the base per se or, for example, as acid addition salt thereof. Until 2008 minocycline base, was known only in the amorphous form.
WO2008102161 describes three crystalline forms of minocycline base which are more stable than the previously known amorphous product.
We have now discovered further new crystalline forms with a better solubility profile and a favorable log P, and these forms have been found to further improve bioavailability and ease of formulation.
According to the present invention, there is provided crystalline minocycline base Form IV as described herein. It is, in particular, characterized by an X-ray powder diffraction pattern having peaks at 8.3; 13.46; 14.1, 21.3; 16.62±0.2° 2θ. It can be further characterized by an X-ray powder diffraction pattern having peaks at 7.06, 8.3, 10.3, 11.18, 13.46, 14.1, 14.94, 16.62, 20.62, 21.3, ±0.2° 2θ.
Crystalline minocycline base Form IV is suitably characterized by an X-ray powder diffraction pattern having peaks as given in FIG. 1.
Crystalline minocycline base Form IV according to the invention preferably shows an endotherm at 146° C. from the STDA signal of a TGA analysis as described herein.
The invention also provides minocycline acid addition salts formed from, or obtainable from, crystalline minocycline base Form IV according to the invention.
In another aspect, there is provided a process for preparing minocycline base Form IV according to the invention and this is preferably characterized by comprising dissolving minocycline base in an aliphatic ketone having 8 carbon atoms or less, or 6 carbon atoms or less, followed by the precipitation of, and optionally isolation of, Form IV. We prefer to use aliphatic secondary ketones. Aliphatic ketones having 4 carbon atoms are preferred. One preferred aliphatic ketone is methyl ethyl ketone (MEK).
The process for preparing minocycline base Form IV according to the invention is preferably characterized by a dissolution/precipitation temperature of from 20 to 25° C. The solution is stirred for at least 30 mins, before any isolation. The solution may, for example, be stirred up to 5 hours, or up to 10 hours, in order to increase the yield of precipitate.
In another aspect of the invention, there is provided crystalline minocycline base Form V characterized, in particular, by an X-ray powder diffraction pattern having peaks at 5.34, 16.74, 21.06, 23.02, 22.26±0.2° 2θ. It is further characterized by an X-ray powder diffraction pattern having peaks at 2.9, 5.34, 7.9, 12.94, 15.06, 16.74, 18.22, 19.78, 21.06, 22.26, 23.02, 25.42±0.2° 2θ.
Crystalline minocycline base Form V according to the invention is suitably characterized by an X-ray powder diffraction pattern having peaks as given in FIG. 4.
Crystalline minocycline base Form V according to the invention preferably shows an endotherm at 140° C. from the STDA signal of a TGA analysis as described herein.
The invention also provides minocycline acid addition salts formed from, or obtainable from, crystalline minocycline base Form V according to the invention.
The invention also provides a process for preparing minocycline base Form V according to the invention characterized by suspending minocycline base in 2-methyl tetrahydrofuran (THF) and applying a thermocycling temperature profile for crystallization, optionally followed by isolation of the crystals.
Preferably, the thermocycling temperature profile comprises heating the suspension three times up to a temperature of about 40° C. (+/−5° C.) and cooling each time to about 5° C. (+/−5° C.). The thermocycling profile shown in FIG. 8 illustrates a suitable regime.
The invention also provides a pharmaceutical composition characterized by comprising crystalline minocycline base Form IV, or an acid addition salt thereof, according to the invention, and optionally one or more pharmaceutically acceptable excipients.
The invention also provides a pharmaceutical composition characterized by comprising crystalline minocycline base Form V, or an acid addition salt thereof, according to the invention, and optionally one or more pharmaceutically acceptable excipients. Acceptable excipients, as well as the types of formulation suitable for delivery of minocycline, will be known to those familiar with this technical area.
The invention also provides a pharmaceutical composition as described herein for use in medicine. Preferably, the pharmaceutical composition is used as an antibacterial agent or as an anti-inflammatory agent.